Inhibition of GSK-3β as a target for cardioprotection: the importance of timing, location, duration and degree of inhibition

AbstractCardiovascular disease is the major cause of morbidity and mortality in western countries such as the US. Myocardial infarction leads to loss of myocytes and with extremely limited ability to replenish cardiomyocytes, the heart exhibits depressed contractility. This ultimately results in hypertrophy of the remaining viable myocytes, which is the primary predictor for heart failure. Thus, drug therapies which can reduce myocyte cell death and reduce postischaemic dysfunction would be expected to greatly reduce cardiac hypertrophy and subsequent heart failure and death. Inhibition of glycogen synthase kinase (GSK)-3β has been proposed as a strategy to improve postischaemic cardiomyocyte survival, as inhibition of GSK-3β has been shown to reduce myocardial cell death following ischaemia and reperfusion. Therapies for inhibiting GSK are feasible as there are a number of newly developed specific inhibitors of GSK available, although most of these drugs have not been tested in long-term animal studies.Keywords:: apoptosiscardiac hypertrophycardioprotectionglycogen synthase kinase (GSK)heartmetabolism